HORMONES ARE NOT BAD FOR YOU BUT BAD SCIENCE IS

In 2002 some scientists published a paper (see ref at end of this article) which said taking hormones after menopause increased risks of heart problems, breast cancer, stroke and blood clots. The news media were quick to exclaim to the world that: BIG BAD HORMONES WERE NOT GOOD FOR YOU.

This caused quite a stir and many physicians advised patients to stop taking their hormone drugs which contained estrogen and progesterone. This is too bad because the conclusions of the Woman’s Health Initiative (WHI) scientist were wrong for the following reasons:

THEY USED THE WRONG CONFIDENCE INTERVAL TO DETERMINE STATISTICAL SIGNIFICANCE

In their first paper, the one in 2002 that caused most of the problems, the WHI authors used a measurement of variation called the nominal 95% confidence interval and they should have used an adjusted 95% confidence interval. Confidence intervals (CIs) are used in tests for statistical significance.



Nominal CIs can be used when a single outcome or result is being tested but in the WHI studies there were multiple outcomes being tested, so they should have used CIs which are adjusted to take into consideration the possible error introduced by multiple testing. Nominal CIs are smaller than adjusted CIs, so when they are used incorrectly they make numbers look significant when they are not.



For example: The relative risk (RR) and nominal CI for risk of breast cancer was 1.26 (1.0-1.59) which is barely significant ; however, when the correct adjusted CI is used (0.83-1.92) we see that it includes the no effect level of 1.0 and would be judged as not significant. This incorrect use of nominal CIs was used throughout the paper.



Such incorrect use of statistical techniques should have disqualified this paper from publication.

ACTUAL AND RELATIVE RISKS

One of the biggest contributions to inaccuracies and exaggerations in these studies is the failure to state and emphasize that the actual or absolute risks are small. How can this be? It is really very simple as I have explained in my two earlier Blogs entitled: What is the truth about health risks? and How to understand blog graphs.



The bottom line is you can have very small actual risks accompanied by very large relative risks. Since the relative risk numbers are large they are the ones that show up in the news media. If the small actual risk numbers were released no one would pay any attention to them.



For more comparisons between relative and actual risk see the table below. Remember these claimed increased risks were not significant in the first place so they don’t count.

FAILURE TO EXAMINE THEIR DATA CAREFULLY

A good example of this lack of attention was their failure to see that the apparent increased risk of heart disease and breast cancer during a critical time (yr 5) was not caused by an increased number of women with these diseases but a chance decrease in the number of women in the placebo control group. There was no real or significant increase in risk in heart disease or breast cancer but these mistakes were the main reason for stopping the study.



Increases and decreases in risks may occur by chance or there may be some underlying cause. The proper statistical analysis tells us whether these differences are real or just due to chance. All too often in these kinds of studies the authors will make statements like: The risk of breast cancer was increased by hormone treatment. Then they add: although the increase was not significant. In other words the differences could have occurred by chance and there is no real increase. The only part of the above which is published in the press is: Breast Cancer Risks Increased by Hormone Treatment. The headline should have been: Breast Cancer Risks Not Increased by Hormone Treatment.



In a subsequent more detailed paper on the effects of hormone treatment these authors indicate that no significant increased risks of breast cancer were observed (Chlebowski et al 2003). This revised conclusion was not announced by the news media and no retraction of the original incorrect conclusions was made. Most doctors and researchers either do not know of this correction or choose to ignore it.





THE WOMEN IN THE STUDY WERE TOO OLD WHEN THE STUDY BEGAN

The WHI studies used data from women who were 12-15 years past menopause before they started taking hormones. This means these women were without their normal levels of estrogen and progesterone long enough to bring about changes in various bodily functions which are the precursors of disease. For instance, ovarian hormones are important for maintaining the blood vascular system in good shape. Once vascular disease has begun as a result of menopause hormone treatment is not likely to reverse the effects. Proper bone strength is maintained by estrogen and when it is no longer secreted at menopause bones begin to lose calcium and the first stages of osteoporosis begin. Most reproductive scientists believe that post menopausal hormones should be used as preventives not corrective therapy.







WHI STUDIES WERE NOT REALLY DOUBLE BLIND



The best way to do a clinical study of this kind is to do it so that neither the participants nor the doctors know who is getting the drug and who is getting the placebo. This was supposed to be one of the strengths of the WHI studies; unfortunately, the women did not remain blind and as many as 45% of them were not only told what group they were in but also given warnings about the possibility of increased risks for heart disease, breast cancer etc. This destroys the credibility of such a study and when this happen the entire study should have been stopped because of these flaws.

ESTROGEN ALONE DID NOT INCREASE RISK OF BREAST CANCER

The WHI investigators also evaluated disease outcomes in women who took estrogen alone as a post-menopausal treatment. The authors concluded that estrogen alone did not increase the risk of breast cancer or heart disease and decreased the risks of hip fracture. They also concluded that estrogen alone did increase the risk of stroke. These four papers, most of which were published in 2006, suffer from the same problems and bad sciences as outlined above. They are loaded with extreme variability in the treated and control groups which were not taken into consideration. Once again, they used the wrong measure of variability to test for significance, and called the increase risk of stroke to be significant when it was not. In addition, these estrogen only studies have all of the other problems discussed for the estrogen plus progestin studies.

CONCLUSIONS

Most people, including physicians, do not realize that the conclusions in the original 2002 paper were incorrect. Although the WHI investigators indicate in their later papers that no increased risks were found, they fail to point out clearly that their conclusions were incorrect in 2002 and that the study should not have been stopped. Little has been said in the popular media. No retraction, no admission that the WHI study should have been continued, no attempt to set the record straight. So most women and many physicians keep plodding along believing hormones increase risks for these diseases, when they don’t.

REFERENCES

Chlebowski RT et al (2003) Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. JAMA 289: 3243



Writing Group for the Women’s Health Initiative Investigators. (2002) Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women’s Health Initiative Randomized Controlled Trial. JAMA:288:321-333.



DIETARY FIBER AND HEART PROBLEMS

Surely high fiber diets are good for you?  I always thought so, but I began to wonder when I looked into the evidence.  This concept has suggested by many people. 

One of these beliefs is that high fiber diets will reduce the risk of heart attacks (myocardial infarcts, MI) and other heart diseases(see Mozaffarian et al for references). This belief comes from a paper by Rimm et al (1996) who claimed to demonstrate such an inverse relationship. This seemed to be a reasonable assumption and one I would like to believe, but after analyzing the data I am not convinced.


In the study by Rimm et al (1996) a total of 43,757 male health professionals 40 to 75 years of age were studied for 6 years. During this time 734 cases of myocardial infarction were documented and these were analyzed with respect to dietary intake of fiber. The results of this study are shown in Figure 1. You can see that no significant effect on MI is seen in any group but group 5 which was the highest intake category (28.9 grams/day).


So if you are willing to spend most of you time eating fiber containing foods all day you might be less likely to have a heart attack. However, anytime you have data points which suddenly go from insignificant, as in category 4, to significant, as in category 5 you should worry that the value in category 5 may be a fluke.

Figure 1. Relative risk of myocardial infarct (MI) and dietary intake of fiber.


Each intake category represents increasing intake of total dietary fiber. The data points are relative risks and 95% confidence intervals taken form the data in table 2 of Rimm et al 1996. The quantity of fiber in the diet increases from 1 to 5.


The next study from this same group involved 39,876 women health professionals who were followed for 6 years (Liu et al 2002). The incidence of cardiovascular disease (CVD) and MI were examined in this study and their results for total dietary fiber intake are shown in Fig 2. No significant associations were observed between total fiber intake and CVD (Fig 2 A), and the women in category 4 showed marginal significant decrease in MI (Fig 2 B). Since all other RR are insignificant these data do not support the contention that dietary fiber intake is associated with a decreased risk of CVD or MI.

Figure 2. A. Relative risk of cardiovascular disease (CVD) and B. myocardial infarct (MI) as a result of dietary intake of total fiber. Data taken from tables 3 and 4 in Liu et al 2002.




These authors also examined the association between the various sources of dietary fiber. If any type of fiber would show a protective effect one would think it would be vegetable fiber. Think again. The data in Figure 3 demonstrated that no decrease or increase in relative risks of CVD or MI result from the consumption of various amounts of vegetable fiber.

Figure 3. Relative risk of cardiovascular disease (CVD) and myocardial infarct (MI) as a result of dietary intake of vegetable fiber. Data taken from table 3 and 4 in Liu et al 2002.


If no associations could be shown with total fiber or vegetable fiber, then surely these would be found with soluble fiber. After all, soluble fiber was thought to be primarily responsible for the cholesterol lowering effect of dietary fiber, hence one would expect great things. Several studies claimed this to be true and were summarized in a meta-analysis by Brown et al 1999. However, if you read this paper carefully you would not expect much effect from soluble fiber. Brown et al 1999 found that the concentrations of total cholesterol and LDL cholesterol in the blood were decreased marginally and no effects on HDL cholesterol and triglycerides were found. The reduction of total cholesterol and LDL cholesterol were minus 0.045 mM ( 0.9%)and 0.057 mM ( 2.7%) respectively which are very small and probably physiologically insignificant effects. The authors point out that increasing soluble fiber intake can make only a small contribution to lowering plasma cholesterol. Little did they know, the effect was not just small but it was without consequence as a factor in decreasing the risk of CVD or MI (Figure 4).

 Figure 4 . Relative risk of cardiovascular disease (CVD) and myocardial infarct (MI) as a result of dietary intake of soluble fiber. Data taken from tables 3 and 4 in Liu et al 2002.


Other types of fiber which were included in this study were cereal fiber, fruit fiber and insoluble fiber. These produced no significant reduction in the risk of CVD or MI.



CONCLUSIONS


Try as they might, all of the kings men could not put the story of fiber and heart problems together again. No evidence of a protective effect on CVD or MI from eating even very large quantities of any kind of fiber was found in these studies.



REFERENCES


Brown L, Rosner B, Willett WW, Sacks FM 1999 Cholesterol lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr 69:30-42.


Liu S et al 2002 A prospective study of dietary fiber intake and risk of cardiovascular disease among women. J Am Coll Cardiol 39:49-56.


Mozaffarian et al 2006 Trans fatty acids and cardiovascular disease. NEJM 354:1601-1613.


Rimm EB et al 1996 Vegetable, fruit and cereal fiber intake and risk of coronary heart disease among men. JAMA 275: 447-51/